The present invention is directed to a process for manufacturing of an asymmetric hollow fibre membrane, which is, among other applications, particularly suitable for plasma separation, but which can also advantageously be used in certain technical applications. Furthermore this invention is directed to such membranes being producible by the process of the invention, and to the use of such membranes for plasma separation, plasma filtration, micro filtration, plasma therapy or cell filtration applications.
Plasma separation or apheresis is a medical technology in which the blood of a donor or patient is separated into the plasma, i.e. the cell free component in blood, and the blood cells. Plasma separation may be conducted for several reasons.
In the therapeutical plasmapheresis the separated plasma of a patient's blood is discarded and replaced by a substitute solution or by donor plasma, and is reinfused into the patient. This approach is useful in the treatment of several diseases and disorders. For example, in immunological diseases the plasmapheresis is useful to exchange antibodies, antigens, immune complexes or immune globulins. In non-immunological diseases the plasmapheresis allows for the depletion of metabolites, degradation products, as well as endogenous and exogenous toxins.
In a variant of therapeutical plasmapheresis, plasma fractionation, the separated plasma of a patient's blood undergoes a second stage of further separation into high molecular and low molecular plasma fractions. The high molecular fraction is discarded, and the low molecular fraction of the plasma and the cellular components of the blood are reinfused into the patient.
In an application, called plasma donation, the separated blood plasma from healthy donors is used for therapeutical plasma exchange, or for the isolation of plasma components for pharmaceutical purposes.
The separation of whole blood into plasma and cellular components can be achieved either by centrifugation or by passing the blood through a plasma separation membrane. During the development of plasmapheresis, discontinuous centrifuges have been used first, which have then, at the beginning of the 70s, been replaced by continuous centrifugation systems.
Centrifugation techniques have the advantage of being fast and cost effective, however, they often suffer from leaving impurities of cells or cell debris in the separated plasma. At the end of the 70s, the first membrane systems have been introduced for the plasmapheresis to overcome the disadvantages of centrifugation systems.
While being related to it, the requirements of plasma separation membranes are quite distinct from the requirements of dialysis membranes. Plasma separation uses the effect of separation by filtration, whereas dialysis rather uses osmosis and diffusion.
Some of the essential design criteria of a plasma separation membrane are the wall-shear rate, the transmembrane pressure drop and the plasma filtration rate.
The wall-shear rate in a hollow fibre membrane system is calculated by the following equation:
      γ    w    =            4      ⁢                          ⁢              Q        B                    N      ⁢                          ⁢      π      ⁢                          ⁢              r        3            wherein N is the number of hollow fibres, having the inner radius r, to which blood flow QB is distributed. By the decrease of the plasma portion the blood flow changes across the length of the hollow fibre. This must be considered in the calculation of the wall-shear rate.
The transmembrane pressure (TMP) is another important parameter which is defined as the difference in pressure between the two sides of the membrane. The transmembrane pressure is the driving force for the membrane separation. In general, an increase in the transmembrane pressure increases the flux across the membrane. The exception to this generalization occurs if a compressible filter cake is present on the surface of the membrane. The transmembrane pressure is calculated by the following equation:
      T    ⁢                  ⁢    M    ⁢                  ⁢    P    =                              P          Bi                +                  P          Bo                    2        -          P      F      wherein PBi is the pressure at the blood entrance, PBo is the pressure at the blood exit, and PF is the pressure on the filtrate side of the membrane (plasma side).
The sieving coefficient determines how much of a compound will be eliminated by a filtration process. The sieving coefficient is defined as the ratio of the concentration of a compound in the filtrate to the concentration of this compound in the blood. A sieving coefficient of “0” means that the compound can not pass the membrane. A sieving coefficient of “1” means that 100% of the compound can pass the membrane. For the design of plasma separation membranes it is desired that the whole spectrum of plasma proteins can pass the filtration membrane whereas the cellular components are completely retained.
The requirements of a plasma separation membrane for plasmapheresis can be summarized as by the following characteristics:                high permeability or high sieving coefficient for the whole spectrum of plasma proteins and lipoproteins;        high surface porosity and total porosity of the membrane to achieve high filtration performance;        a hydrophilic, spontaneously wettable membrane structure;        low fouling properties for long term stable filtration;        low protein adsorption;        smooth surfaces in contact with blood;        low or no tendency to haemolysis during blood processing;        constant sieving properties and filtration behaviour over the whole treatment period;        high biocompatibility, no complement activation, low thrombogenicity;        mechanical stability;        sterilizability by steam, gamma radiation and/or ETO;        low amount of extractables.        